Recent studies have implicated neurotensin and gamma-endorphin fragments of beta endorphin as potential "endogenous neuroleptics". Our hypothesis is directed at determining if neuroleptic drugs such as haloperidol and chlorpromazine versus centrally acting non-neuroleptics such as apomorphine or promethazine alter the synaptosomal levels or metabolism of neurotensin and/or beta-endorphin in specific brain regions associated with known anatomical projections of these peptidergic systems under consideration. To accomplish our goals, we will use in vivo perfusions of drugs coupled to in vitro incubations for specific tissue organelles with neurotensin and beta-endorphin to determine if the proteolytic metabolism of these peptides is altered. HPLC separations of peptides formed will be coupled to RIA for synaptosomal content of peptides and fragments. A disruption in the synaptosomal levels and/or metabolism of beta- endorphin or neurotensin could lead to an imbalance in homeostatic levels of these peptides. This disruption may be associated with neuroleptic drug treatment causing some of the side effects noted by patients taking these drugs. Therefore, the long-term objective of this proposal is to provide a better understanding of the mode of action of haloperidol and chlorpromazine through peptidergic mechanisms. Since these two drugs are commonly proscribed neuroleptics, it is very important that we clearly understand their effect on beta-endorphin and neurotensin.